Covering the whole development process for the global biotechnology industry

Bioprocessing begins upstream, most often with culturing of animal or microbial cells in a range of vessel types (such as bags or stirred tanks) using different controlled feeding, aerating, and process strategies.

Beginning with harvest of material from a bioreactor, downstream processing removes or reduces contaminants to acceptable levels through several steps that typically include centrifugation, filtration, and/or chromatographic technologies.

Drug products combine active pharmaceutical ingredients with excipients in a final formulation for delivery to patients in liquid or lyophilized (freeze-dried) packaged forms — with the latter requiring reconstitution in the clinical setting.

Many technologies are used to characterize biological products, manufacturing processes, and raw materials. The number of options and applications is growing every day — with quality by design (QbD) giving impetus to this expansion.

Even as it matures, the biopharmaceutical industry is still a highly entrepreneurial one. Partnerships of many kinds — from outsourcing to licensing agreements to consultancies — help companies navigate this increasingly global business environment.

Cancer Immunotherapies: Fulfilling the Promise of Protein and Cell Therapies

With few exceptions, both small-molecule and biological cancer treatments have contributed only incrementally towards achieving long-term responses or outright cures. In this regard, emerging cell- and protein-based cancer immunotherapies represent game-changing strategies for treating even refractory cancer. With long-term responses now possible, medical science may be on the verge of delivering on the long-unfulfilled promise of making cancer a manageable disease.

But impediments to commercializing cancer immunotherapies are substantial. Producing cell-based treatments entails substantial hands-on manipulation and perfecting the logistics of harvesting and expanding therapeutic cells and delivering them to patients. Given the handling requirements and high cost of goods (CoG) for cell-based immunotherapies, reimbursement considerations will force developers to demonstrate indisputable value. Those developing immunotherapies based on monoclonal antibodies (MAbs) will experience fewer such issues thanks to platform manufacturing technologies, but even they are likely to be priced to perfection.

Issues In Protein Immunotherapy
Immunotherapy Squared: Bavituximab, a monoclonal antibody from Peregrine Pharmaceuticals (Tustin, CA), is a classic protein immunotherapy targeting phosphatidylserine (PS), a novel immune system checkpoint. PS exists on the inside membrane layer of every cell, but it externalizes when cells die. “In circulation, PS signals the immune system to engulf dying cells,” explains Steve King, Peregrine’s chief executive officer (CEO). PS also limits the immune response. As tumors proliferate, they often outgrow their blood supply so that many cells die, sending more PS into circulation. Tumors also release microparticles containing PS, ultimately suppressing immune response to the tumor by keeping the host’s immune system busy fighting particles and dead cells.

Peregrine’s collaboration with AstraZeneca for clinical development could be described as “immunotherapy squared.” Bavituximab’s presumed mode of action is to block immunosuppression while activating a tumor-killing T-cell immune response. AstraZeneca’s investigational anti-PD-L1 immune checkpoint inhibitor, durvalumab, targets the programmed cell death ligand PD-L1, which helps tumors go undetected by the immune system. Both companies believe that combining the enhanced T-cell–mediated antitumor activity with a checkpoint inhibitor will extend the ability of tumor-specific T-cells to attack cancerous cells.

Like many small biopharmaceutical companies with a promising pipeline product, Peregrine chooses to emphasize clinical development over manufacturing or process development, confident that if bavituximab succeeds in the clinic, then CoG issues will resolve themselves. “Our process flexibility assures that we could duplicate the entire facility and all its infrastructure in an open warehouse space almost anywhere,” King affirms. “We built the current facility with the idea of supporting production lots early in commercialization. At that point you have substantial revenue, so all your manufacturing avenues open up. And the risk of sticking with the same systems, at the same scale, from a comparability standpoint is negligible.”

Downstream operations could very well become a bottleneck. Peregrine has learned through its contract manufacturing business, Avid Bioservices, that high yields — even from 1,000-L or 2,000-L bioreactors — impose operational and financial pressures on downstream processing and purification. Protein A affinity chromatography columns, for example, begin at about $1 million for resin alone and go up from there. “That’s a big investment for a small-to-midsized company,” King admits. Peregrine is handling such challenges through a hybrid approach of maintaining a revenue-generating manufacturing business that mitigates the cost of preparing for commercialization of its own products. “Not many companies have that flexibility.”

Blocking the Immunity Blockers: In November 2015, Faron Pharmaceuticals (Turku, Finland) entered into an agreement with Swiss company Selexis through which Faron will access the Selexis SUREtechnology platform system and SURE CHO-M cell line expression technology. Faron will use them to develop high-expressing and stable clonal cell lines for production of its Clevegen cancer immunotherapy antibody. The Selexis technologies rapidly generate high antibody-expressing clonal cells with predictable titers and genetic stability.

Immune defenses are often suppressed in cancer patients. Faron’s product targets the cell-surface receptor Clever-1 on the surfaces of tumors’ vascular endothelial cells and tumor-associated macrophages (TAMs). Binding of the drug to Clever-1 prevents TAM accumulation around tumors and decreases their antiinflammatory function, allowing a patient’s natural tumor-fighting immunity to take over. Thus, the Clevegen antibody cleverly and indirectly stimulates a patient’s immune system to fight his or her tumor.

According to Faron, the Clevegen antibody is well differentiated from competing products by its ability to specifically target TAMs of the M2 variety (which facilitate tumor growth) while sparing M1 macrophages that support antitumor immune activation and desirable immunity in general. Chief executive officer Markku Jalkanen likens immune-suppressive mechanisms with a shrink-wrap that keeps beneficial immune cells at bay. “These mechanisms block immune recognition cells from entering. If these suppressants are not removed, even activated T cells cannot reach the tumor.”

Depending on the jurisdictions in which it is licensed, Clevegen probably will be approved as a combination or salvage therapy. But the company cites a strong scientific justification for it as a first-line treatment. “The reason we are interested in standalone therapy is we can recognize Clever-1–positive monocytic cells in circulation in cancer patients,” Jalkanen explains. “So we may already have a surrogate end-marker for both disease and efficacy of treatment, levels of which we can determine through flow cytometry.” With a test available, Faron could identify patients who have higher levels of protumor macrophages and thus are most likely to benefit from Clevegen therapy.

Cell-Based Immunotherapies
An Existential Challenge: Cell-based immunotherapies fall into two categories. Autologous treatments, by far the more common in the development pipeline, are based on manipulating an individual’s own (immune) cells, usually expanding them ex vivo, and reinjecting them into the same patient. Allogeneic treatments use banked cells from a common source.

Manufacturing is the critical — some might say existential — challenge for autologous cell-based immunotherapies. “These therapies emerged from academic centers, so production needs to catch up with the equivalent innovation that has occurred during discovery,” explains Jim Faulkner, head of manufacturing at Autolus (London, UK) and editorial advisor to BioProcess International. Three key enablers for success will be automation, single-use technologies, and sophisticated logistics. “It really is a very different paradigm from the conventional supply chain model that has dominated the pharmaceutical business to date. New service providers are emerging to offer creative solutions to the manufacturing challenges that T-cell therapies present.”

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With a PhD in organic chemistry from the State University of New York at Stony Brook, freelance writer Angelo DePalma (angelodp@gmail.com) was a chemist first at Brookhaven National Laboratory and then at Schering-Plough. For over 25 years, he has written for dozens of technical online and print publications, as well as product and service companies in biotechnology, bioprocessing, pharmaceutical chemistry, pharmaceutical development, drug discovery, and laboratory instrumentation.